Weekly Sepsis Research Analysis
This week’s sepsis literature spanned translational mechanisms, metabolic adjuncts to enhance antimicrobials, and clinically actionable hemodynamic/implementation insights. High-impact mechanistic work defined druggable neuroimmune and macrophage axes (dopamine–DRD2–ACOD1 and STAT1–ZBP1) with translational signals in animals and patient correlations. Preclinical data showed fasting/ketogenesis (acetoacetate) markedly sensitizes Gram-negative bacteria to antibiotics, opening adjunctive therapies,
Summary
This week’s sepsis literature spanned translational mechanisms, metabolic adjuncts to enhance antimicrobials, and clinically actionable hemodynamic/implementation insights. High-impact mechanistic work defined druggable neuroimmune and macrophage axes (dopamine–DRD2–ACOD1 and STAT1–ZBP1) with translational signals in animals and patient correlations. Preclinical data showed fasting/ketogenesis (acetoacetate) markedly sensitizes Gram-negative bacteria to antibiotics, opening adjunctive therapies, while large-cohort and registry studies advanced trajectory-based prognostics and optimized vasopressor and stewardship strategies.
Selected Articles
1. A neuroimmune pathway drives bacterial infection.
This translational mechanistic study identifies dopamine as a regulator of ACOD1 transcription via a DRD2–TLR4 complex that modulates MAPK3–CREB1 signaling, leading to PD-L1–mediated immunosuppression in sepsis. In murine bacterial sepsis, dopamine agonism (pramipexole) reduced lethality even when given late; a dopamine antagonist worsened outcomes. Dysregulation of the dopamine–ACOD1 axis correlated with severity in human patients, highlighting a druggable neuroimmune target.
Impact: Delineates a druggable neuroimmune axis linking neurotransmission and immunometabolism with mechanistic depth and translational signals in animals and patients, opening repurposing opportunities for dopaminergic agents in sepsis.
Clinical Implications: Supports evaluation of dopaminergic modulation (e.g., pramipexole) as adjunctive immunomodulation in bacterial sepsis and cautions about dopamine antagonists in septic patients; suggests biomarkers along the DRD2–ACOD1–PD-L1 axis for stratification.
Key Findings
- Dopamine via DRD2 inhibits LPS-induced ACOD1 expression in innate immune cells.
- DRD2 forms a complex with TLR4 to trigger MAPK3-dependent CREB1 phosphorylation and ACOD1 transcription.
- ACOD1 upregulation induces PD-L1 production independently of itaconate, promoting immunosuppression.
- Delayed pramipexole reduced lethality in murine bacterial sepsis; aripiprazole increased mortality.
- Dopamine–ACOD1 axis dysregulation correlated with sepsis severity in patients.
2. Fasting-induced ketogenesis sensitizes bacteria to antibiotic treatment.
Preclinical work across multiple murine models of Gram-negative sepsis found that fasting-induced ketogenesis, and specifically the ketone body acetoacetate, potentiates antibiotic efficacy, increases bacterial clearance, and improves survival. Mechanistically, acetoacetate increases bacterial membrane permeability, depletes positively charged amino acids and putrescine, and amplifies antibiotic lethality. Antibiotic-plus-ketone body combination therapy recapitulated fasting benefits.
Impact: Uncovers a modifiable host metabolic state (ketogenesis/acetoacetate) that markedly increases antibiotic lethality against key Gram-negative pathogens, offering a novel adjunctive therapeutic paradigm with strong translational potential.
Clinical Implications: Motivates early-phase human trials of ketone-body supplementation or controlled metabolic modulation as adjuncts to antibiotics in bacterial sepsis; safety, timing, dosing, and patient selection (e.g., pathogen type, nutritional status) must be established before clinical use.
Key Findings
- Fasting potentiated antibiotic treatment in murine sepsis models (Salmonella, Klebsiella, Enterobacter), improving bacterial clearance and survival.
- Acetoacetate increased outer and inner bacterial membrane permeability and antibiotic lethality.
- Acetoacetate depleted bacterial positively charged amino acids and putrescine, causing membrane dysfunction and redox-related lethality.
- Antibiotic-plus-ketone body therapy recapitulated fasting benefits in vivo.
3. Myeloid deficiency of Z-DNA binding protein 1 restricts septic cardiomyopathy via promoting macrophage polarisation towards the M2-subtype.
Using sc/snRNA-seq, genetic knockouts, and pharmacologic validation, this preclinical study shows that ZBP1 expression in macrophages (induced via STAT1) drives LPS-induced septic cardiomyopathy by promoting M1 polarization and inflammatory infiltration. Global and myeloid-specific ZBP1 deletion, and STAT1 inhibition (fludarabine), shifted macrophages toward M2, reduced inflammation, improved cardiac function, and increased survival, nominating the STAT1–ZBP1 axis as a therapeutic target.
Impact: Identifies a macrophage-intrinsic, drug-modulable pathway (STAT1→ZBP1) causally linked to septic cardiac dysfunction with genetic and pharmacologic rescue, providing a concrete translational target to address a major organ-specific sepsis complication.
Clinical Implications: Supports exploring STAT1 inhibition or ZBP1-targeted strategies to prevent or treat septic cardiomyopathy; next steps should validate biomarker expression in human cardiac/sepsis cohorts and test safety/efficacy in polymicrobial sepsis models before clinical trials.
Key Findings
- ZBP1 expression is upregulated in myocardial tissue after LPS and is mainly expressed in macrophages by sc/snRNA-seq.
- Global and myeloid-specific Zbp1 deletion promotes M2 polarization, reduces inflammatory infiltration, and improves cardiac function and survival.
- STAT1 drives ZBP1 transcription; STAT1 inhibition (fludarabine) reproduces the protective M2 phenotype and functional rescue.